DESCRIPTION (Adapted from the Application Abstract): Local stimuli regulate the activity of Src-family tyrosine kinases (SFKs) present on the apical surface of epithelial cells. The SFK Yes is compartmentalized at the apical membrane by indirect interaction with the subapical scaffolding protein ERM phosphoprotein 50 (EBP50) that also associates with Cystic Fibrosis transmembrane regulator (CFTR) and ENaC. The proposed experiments will: 1) identify SFK's that regulate ion transport in the airway; 2) chracterize interactions that are involved in forming multiprotein complexes containing ENaC and SFK's; and 3) identify luminal stimuli that activate apical SFK's to modulate apical ion transport and determine how SFK's regulate the activities of ion channels. Together, the experiments will critically test the hypothesis that local regulation of apical ion transport in airway epithelia requires the formation of apical signaling complexes, and that one critical component of these complexes is a SFK.